Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
Carcinogenesis. 2009 Dec;30(12):1987-96. doi: 10.1093/carcin/bgp158.
Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.
癌细胞在逃脱免疫系统后转移到其他部位，CD70、CD44 和血管内皮生长因子 (VEGF) 在这个过程中发挥重要作用。最近有报道称，白细胞介素 (IL)-18 与皮肤肿瘤的发病机制密切相关。因此，我们研究了内源性 IL-18 从胃癌对免疫逃逸机制和转移通过调节 CD70、CD44 和 VEGF 的表达。IL-18 和 IL-18R 的表达不仅在肿瘤组织 (n = 10) 和血清 (n = 20) 来自胃癌患者，但也在人胃癌细胞系。IL-18 和 IL-18R 的表达被发现在胃癌细胞系和肿瘤组织。此外，IL-18 水平升高在血清从癌症患者 (P < 0.05)，与正常个体的血清相比。通过流式细胞术、免疫印迹和酶联免疫吸附试验改变 CD70、CD44 和 VEGF 的表达和免疫敏感性 (51)Cr 释放试验，沉默或中和内源性 IL-18 后。CD70 表达增加，它增加癌细胞的免疫敏感性。相比之下，CD44 和 VEGF 表达减少，它抑制肿瘤新生血管形成和胃癌的转移。IL-18 小干扰 RNA (siRNA) 转染胃癌细胞接种 Balb/C (nu/nu) 小鼠后，通过测量肿瘤大小来确定肿瘤体积的消退。通过苏木精和伊红染色研究转移病灶的数量和位置。在注射 IL-18 siRNA 转染细胞系的小鼠中观察到肿瘤质量的消退和转移的抑制。我们的数据表明，内源性 IL-18 可能通过抑制 CD70 和上调 CD44 和 VEGF 来增强转移能力，从而促进胃癌细胞的免疫逃逸。
